Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland. Leibniz Institute for Prevention Research and Epidemiology, BIPS, Bremen, Germany.
Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
Clin Cancer Res. 2015 Apr 15;21(8):1951-61. doi: 10.1158/1078-0432.CCR-14-0122. Epub 2014 Sep 23.
Morphologic intratumor heterogeneity is well known to exist in hepatocellular carcinoma (HCC), but very few systematic analyses of this phenomenon have been performed. The aim of this study was to comprehensively characterize morphologic intratumor heterogeneity in HCC. Also, taken into account were well-known immunohistochemical markers and molecular changes in liver cells that are considered in proposed classifications of liver cell neoplasms or discussed as molecular therapeutic targets.
In HCC of 23 patients without medical pretreatment, a total of 120 tumor areas were defined. Analyzed were cell and tissue morphology, expression of the liver cell markers cytokeratin (CK)7, CD44, α-fetoprotein (AFP), epithelial cell adhesion molecule (EpCAM), and glutamine synthetase (GS) along with mutations of TP53 and CTNNB1, assayed by both Sanger and next-generation sequencing.
Overall, intratumor heterogeneity was detectable in the majority of HCC cases (20 of 23, 87%). Heterogeneity solely on the level of morphology was found in 6 of 23 cases (26%), morphologic heterogeneity combined with immunohistochemical heterogeneity in 9 of 23 cases (39%), and heterogeneity with respect to morphologic, immunohistochemical, and mutational status of TP53 and CTNNB1 in 5 of 23 cases (22%).
Our findings demonstrate that intratumor heterogeneity represents a challenge for the establishment of a robust HCC classification and may contribute to treatment failure and drug resistance in many cases of HCC.
肝细胞癌（HCC）中存在肿瘤内形态异质性是众所周知的，但对此现象的系统分析却很少。本研究旨在全面描述 HCC 中的肿瘤内形态异质性。此外，还考虑了已知的免疫组织化学标志物和肝细胞的分子变化，这些标志物和分子变化被认为是肝细胞肿瘤分类中的标准，或者被讨论为分子治疗靶点。
在未经医学预处理的 23 例 HCC 患者中，共定义了 120 个肿瘤区域。分析了细胞和组织形态、细胞角蛋白（CK）7、CD44、甲胎蛋白（AFP）、上皮细胞黏附分子（EpCAM）和谷氨酰胺合成酶（GS）的表达以及 TP53 和 CTNNB1 的突变，这些突变通过 Sanger 和下一代测序进行检测。
总体而言，大多数 HCC 病例（23 例中的 20 例，87%）中均可检测到肿瘤内异质性。23 例中有 6 例（26%）仅存在形态学异质性，23 例中有 9 例（39%）存在形态学和免疫组织化学异质性，23 例中有 5 例（22%）存在形态学、免疫组织化学和 TP53 及 CTNNB1 突变状态的异质性。
我们的研究结果表明，肿瘤内异质性是建立稳健 HCC 分类的一个挑战，并且可能导致许多 HCC 病例的治疗失败和耐药。
